Background: Breast cancer (BC) is a heterogeneous malignant tumor, leading to the second major cause of female mortality. This study aimed to establish an in-depth relationship between ferroptosis-related LncRNA (FRlncRNA) and the prognosis as well as immune microenvironment of the patients with BC.Methods: We downloaded and integrated the gene expression data and the clinical information of the patients with BC from The Cancer Genome Atlas (TCGA) database. The co-expression network analysis and univariate Cox regression analysis were performed to screen out the FRlncRNAs related to prognosis. A cluster analysis was adopted to explore the difference of immune microenvironment between the clusters. Furthermore, we determined the optimal survival-related FRLncRNAs for final signature by LASSO Cox regression analysis. Afterward, we constructed and validated the prediction models, which were further tested in different subgroups.Results: A total of 31 FRLncRNAs were filtrated as prognostic biomarkers. Two clusters were determined, and C1 showed better prognosis and higher infiltration level of immune cells, such as B cells naive, plasma cells, T cells CD8, and T cells CD4 memory activated. However, there were no significantly different clinical characters between the clusters. Gene Set Enrichment Analysis (GSEA) revealed that some metabolism-related pathways and immune-associated pathways were exposed. In addition, 12 FRLncRNAs were determined by LASSO analysis and used to construct a prognostic signature. In both the training and testing sets, patients in the high-risk group had a worse survival than the low-risk patients. The area under the curves (AUCs) of receiver operator characteristic (ROC) curves were about 0.700, showing positive prognostic capacity. More notably, through the comprehensive analysis of heatmap, we regarded LINC01871, LINC02384, LIPE-AS1, and HSD11B1-AS1 as protective LncRNAs, while LINC00393, AC121247.2, AC010655.2, LINC01419, PTPRD-AS1, AC099329.2, OTUD6B-AS1, and LINC02266 were classified as risk LncRNAs. At the same time, the patients in the low-risk groups were more likely to be assigned to C1 and had a higher immune score, which were consistent with a better prognosis.Conclusion: Our research indicated that the ferroptosis-related prognostic signature could be used as novel biomarkers for predicting the prognosis of BC. The differences in the immune microenvironment exhibited by BC patients with different risks and clusters suggested that there may be a complementary synergistic effect between ferroptosis and immunotherapy.

Extracellular vesicles (EVs) can regulate the polarization of macrophages in a variety of inflammatory diseases by mediating intercellular signal transduction and affecting the occurrence and development of diseases. After macrophages are regulated by EVs, they mainly show two phenotypes: the proinflammatory M1 type and the anti-inflammatory M2 type. A large number of studies have shown that in diseases such as mastitis, inflammatory bowel disease, Acute lung injury, and idiopathic pulmonary fibrosis, EVs promote the progression of the disease by inducing the M1-like polarization of macrophages. In diseases such as liver injury, asthma, and myocardial infarction, EVs can induce M2-like polarization of macrophages, inhibit the inflammatory response, and reduce the severity of the disease, thus indicating new pathways for treating inflammatory diseases. The EV/macrophage axis has become a potential target for inflammatory disease pathogenesis and comprehensive treatment. This article reviews the structure and function of the EV/macrophage axis and summarizes its biological functions in inflammatory diseases to provide insights for the diagnosis and treatment of inflammatory diseases.

Breast cancer is the second most prevalent cancer in women worldwide. Long non-coding RNAs (lncRNAs) have been identified as important regulators of tumorigenesis and tumor metastasis. lncRNA FGD5-AS1 has been previously reported as a carcinogenic gene, however its role in breast cancer has yet to be investigated. The present study aimed to understand the function of lncRNA FGD5-AS1 in breast cancer and examine the underlying molecular mechanisms. Sample tissues for downstream gene expression profiling were collected from patients with breast cancer (n=23). The effect of FGD5-AS1 overexpression on cell viability, invasion and migration has been studied in breast cancer cells (MDA-MB-231). Changes in glycolysis were monitored by comparing glucose consumption, lactate production and ATP levels. Using StarBase and TargetScan databases a putative interaction between FGD5-AS1, miR-195-5p and SNF1-like kinase 2 (NUAK2) was predicted in silico . Expression levels of FGD5-AS1, has-miR-195-5p and NUAK2 were validated by reverse transcription-quantitative PCR and interactions were validated using dual-luciferase reporter assays and RNA pull-down. High expression of lncRNA FGD5-AS1 was detected in breast cancer tissue samples and disease model cell lines. Silencing of FGD5-AS1 led to decreased cell proliferation, migration and invasion. It was identified that at a molecular level FGD5-AS1 serves as a sponge of miR-195-5p and alters the expression of its downstream target gene NUAK2. In breast cancer lncRNA FGD5-AS1 serve a key role in glycolysis and tumor progression via the miR-195-5p/NUAK2 axis. The findings of the present study indicated FGD5-AS1 as a candidate target for intervention in patients with breast cancer.

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Objective: N6-methyladenosine (m6A) modification may modulate various biological processes. Nonetheless, clinical implications of m6A modification in pancreatic cancer are undefined. Herein, this study comprehensively characterized the m6A modification patterns in pancreatic cancer based on m6A regulators.Methods: Genetic mutation and expression pattern of 21 m6A regulators and their correlations were assessed in pancreatic cancer from TCGA dataset. m6A modification patterns were clustered using unsupervised clustering analysis in TCGA and ICGC datasets. Differences in survival, biological functions and immune cell infiltrations were assessed between modification patterns. A m6A scoring system was developed by principal component analysis. Genetic mutations and TIDE scores were compared between high and low m6A score groups.Results: ZC3H13 (11%), RBM15B (9%), YTHDF1 (8%), and YTHDC1 (6%) frequently occurred mutations among m6A regulators. Also, most of regulators were distinctly dysregulated in pancreatic cancer. There were tight crosslinks between regulators. Two m6A modification patterns were constructed, with distinct prognoses, immune cell infiltration and biological functions. Furthermore, we quantified m6A score in each sample. High m6A scores indicated undesirable clinical outcomes. There were more frequent mutations in high m6A score samples. Lower TIDE score was found in high m6A score group, with AUC = 0.61, indicating that m6A scores might be used for predicting the response to immunotherapy.Conclusion: Collectively, these data demonstrated that m6A modification participates pancreatic cancer progress and ornaments immune microenvironment, providing an insight into pancreatic cancer pathogenesis and facilitating precision medicine development.

The present study was performed to explore whether and how impaired autophagy could modulate calcium/calmodulin-dependent protein kinase II (CAMKII)-regulated necrosis in the pathogenesis of acute pancreatitis (AP). Wistar rats and AR42J cells were used for AP modeling. When indicated, genetic regulation of CAMKII or ATG7 was performed prior to AP induction. AP-related necrotic injury was positively regulated by the incubation level of CAMKII. ATG7 positively modulated the level of CAMKII and necrosis following AP induction, indicating that there might be a connection between impaired autophagy and CAMKII-regulated necrosis in the pathogenesis of AP. microRNA (miR)-30b-5p was predicted and then verified as the upstream regulator of CAMKII mRNA in our setting of AP. Given that the level of miR-30b-5p was negatively correlated with the incubation levels of ATG7 after AP induction, a rescue experiment was performed and indicated that the miR-30b-5p mimic compromised ATG7 overexpression-induced upregulation of CAMKII-regulated necrosis after AP induction. In conclusion, our results indicate that ATG7-enhanced impaired autophagy exacerbates AP by promoting regulated necrosis via the miR-30b-5p/CAMKII pathway.

Numerous microRNAs (miRNAs) have been demonstrated to be downregulated or upregulated in hepatocellular carcinoma (HCC) and play important roles in its occurrence and development. Therefore, the investigation of miRNAs and their functions implicated in the genesis and development of HCC may provide key clues for the identification of effective therapeutic approaches for patients with this disease. The aims of the present study were to detect miRNA-466 (miR-466) expression in HCC tissues and cell lines and to determine its effects on HCC cell proliferation, apoptosis and metastasis, as well as to explore the mechanisms underlying the tumor-suppressing roles of miR-466 in HCC. In the present study, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to detect miR-466 expression in HCC tissues and cell lines. The effects of miR-466 upregulation on HCC cell proliferation, apoptosis, migration and invasion were determined using Cell Counting Kit-8 assay, flow cytometry analysis and Transwell chamber assay, respectively. The potential target gene of miR-466 was predicted using bioinformatic analysis, which was further confirmed by luciferase reporter assay, RT-qPCR and western blot analysis. It was found that miR-466 was obviously decreased in HCC tissues and cell lines. The results of functional experiments revealed that restoration of miR-466 expression suppressed the proliferation, induced apoptosis, and reduced the metastasis of HCC cells. In addition, metadherin (MTDH) was identified as a direct target of miR-466 in HCC cells. Furthermore, MTDH was upregulated in HCC tissues, which was inversely correlated with the miR-466 level. Moreover, inhibition of MTDH displayed similar tumor-suppressing roles as miR-466 upregulation in HCC cells. In addition, MTDH reintroduction restored the tumor-suppressor activity of miR-466 overexpression in HCC cells. These findings suggest that miR-466 is a potential therapeutic tool for HCC therapy.

Objective: Necroptosis represents a new target for cancer immunotherapy and is considered a form of cell death that overcomes apoptosis resistance and enhances tumor immunogenicity. Herein, we aimed to determine necroptosis subtypes and investigate the roles of necroptosis in pancreatic cancer therapy.Methods: Based on the expression of prognostic necroptosis genes in pancreatic cancer samples from TCGA and ICGC cohorts, a consensus clustering approach was implemented for robustly identifying necroptosis subtypes. Immunogenic features were evaluated according to immune cell infiltrations, immune checkpoints, HLA molecules, and cancer–immunity cycle. The sensitivity to chemotherapy agents was estimated using the pRRophetic package. A necroptosis-relevant risk model was developed with a multivariate Cox regression analysis.Results: Five necroptosis subtypes were determined for pancreatic cancer (C1∼C5) with diverse prognosis, immunogenic features, and chemosensitivity. In particular, C4 and C5 presented favorable prognosis and weakened immunogenicity; C2 had high immunogenicity; C1 had undesirable prognosis and high genetic mutations. C5 was the most sensitive to known chemotherapy agents (cisplatin, gemcitabine, docetaxel, and paclitaxel), while C4 displayed resistance to aforementioned agents. The necroptosis-relevant risk model could accurately predict prognosis, immunogenicity, and chemosensitivity.Conclusion: Our findings provided a conceptual framework for comprehending necroptosis in pancreatic cancer biology. Future work is required for evaluating its relevance in the design of combined therapeutic regimens and guiding the best choice for immuno- and chemotherapy.